-Amyloid-tau framework would apply to research, not clinical care

Researchers for the National Institute on Aging (NIA) and the Alzheimer's Association (AA) have proposed a new biomarker-based definition of Alzheimer's disease for research purposes.

In this framework, Alzheimer's disease -- for observational and interventional research only, not routine clinical care -- would be defined by measurable, underlying pathologic processes that could be documented by biomarkers or autopsy, Clifford R. Jack, Jr., MD, of the Mayo Clinic in Rochester, Minn., and colleagues wrote in Alzheimer's & Dementia.

"The new framework shifts the definition of Alzheimer's in living people from syndromal to a biological construct," Jack told MedPage Today. It updates diagnostic guidelines the NIA and AA established in 2011 for preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease and comes on the heels of FDA policy changes to consider approving Alzheimer's drugs on biomarker changes, not clinical benefit.

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A new definition of Alzheimer's disease (AD), defined by measurable, underlying pathologic processes that could be documented by biomarkers or autopsy, has been proposed for research purposes but not for routine clinical care.

Note that the new framework shifts the definition of Alzheimer's in living people from a syndrome to a biological construct, whereas historically AD has been defined as a clinical syndrome, a progressive decline in cognitive abilities with a prominent memory component, eventually leading to loss of independence.

If the new framework is adopted, patients involved in disease-modifying trials will undergo biomarker tests, Jack noted. "Our hope is that, by defining the disease biologically, clinical trials will be far more effective than they have been in the past and will enroll only people who actually have the disease they're being treated for." Likewise, natural history studies may be able to identify risk factors for Alzheimer's disease with greater precision.

Historically, Alzheimer's disease has been defined as a clinical syndrome, a progressive decline in cognitive abilities with a prominent memory component that eventually led to loss of independence which was termed possible or probable Alzheimer's disease.

Over time, "possible or probable Alzheimer's disease was shortened just to Alzheimer's disease," Jack said. In both medicine and popular concept, dementia became equated with Alzheimer's disease, which posed a problem: up to 30% of people who were considered to have Alzheimer's disease did not have amyloid plaques and tau tangles.

With the new framework, Alzheimer's disease will be defined by beta amyloid deposition and pathologic tau. A person with biomarker evidence of both amyloid beta and pathologic tau would be classified as having Alzheimer's disease. A person with biomarker evidence of amyloid deposition and a normal pathologic tau biomarker would be labeled as having "Alzheimer's pathologic change." Alzheimer's disease and Alzheimer's pathologic change would be phases along the Alzheimer's continuum, independent of clinical symptoms.

Neurodegenerative biomarkers and cognitive symptoms -- neither of which is specific to Alzheimer's disease -- would be used only to stage severity, not to define the presence of the Alzheimer's continuum. The researchers outlined two possible ways to stage disease severity: one that used the three traditional syndromal categories, the other a six-stage numeric scheme.

This amyloid-tau-neurodegeneration (ATN) classification system includes both a cerebrospinal fluid (CSF) and imaging biomarker in each group. New biomarkers could be added to the three ATN groups, and new biomarker groups beyond ATN could be added as they become available.

"Though it has undergone intense scrutiny and an extended period of public comment, this NIA-AA research framework is not a finished product; it is a research proposal," said Maria Carrillo, PhD, the AA's chief science officer.

"This proposal needs to be examined in natural history studies and in clinical trials, especially in diverse populations," Carillo told MedPage Today. "And, for most effective implementation, there needs to be more widespread availability of Alzheimer's biomarkers -- especially, development of valid plasma based biomarkers."

In a related article, James Hendrix, PhD, and members of the AA's Research Roundtable observed several hurdles to implementing the proposed framework in research. "Obtaining biomarkers by either CSF or by imaging adds expense and burden to any study and involves invasive procedures and/or exposure to radiation," the group wrote. PET imaging often is not available outside of major medical centers, and multiple procedures may be needed to inform each of the three legs of the ATN framework.

Biomarker tests themselves also present challenges. Most fluid biomarker assays use CSF, yet blood-based biomarkers would be less expensive and more accessible. And some assays have limited technical and clinical validation, or inter-batch and cross-site variability.

But the benefits might outweigh the costs, Hendrix et al said: The proposed ATN framework could ensure that the right people are studied and provide more precise staging of patients along the Alzheimer's disease continuum. Researchers could investigate whether modulating a certain target interferes with a specific component of disease pathology, for example. And trials in biologically defined populations may help answer questions that have stymied Alzheimer's disease drug development for years.

Last Updated April 10, 2018

Jack reported a relationship with Eli Lilly. Other co-authors reported relationships with various pharmaceutical and diagnostics companies with commercial interests in Alzheimer's disease.

Several of Hendrix's co-authors were employees of pharmaceutical companies including Biogen, Roche, Genentech, Lilly, Pfizer, Lundbeck, and Janssen.

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